Azalactam compounds as HPK1 inhibitors
This invention relates to compounds of general Formula I and pharmaceutically acceptable salts thereof, in which R 1 , R 2 , R 3a , R 3b , and R 4 are as defined herein, to pharmaceutical compositions comprising such compounds and salts, and to methods of using such compounds, salts and compositions for the treatment of abnormal cell growth, including cancer.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
R 1 is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, —N(R 5 )(R 6 ), or (C 3 -C 6 )cycloalkyl, wherein said (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, and (C 3 -C 6 )cycloalkyl are substituted with 0 or 1 substituent that is hydroxy, cyano, (C 1 -C 6 )alkyl, or (C 1 -C 6 )alkoxy, wherein:
R 5 and R 6 are each independently hydrogen or (C 1 -C 6 )alkyl that is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halogen, (C 1 -C 6 )alkoxy, cyano, and hydroxy, or
R 5 and R 6 taken together with the nitrogen to which they are attached form a (4- to 8-membered)heterocycloalkyl that is substituted with 0, 1, or 2 substituents independently selected from the group consisting of halogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy;
R 2 is N(R 7 )(R 8 ), wherein:
R 7 and R 8 are each independently hydrogen or (C 1 -C 6 )alkyl that is substituted with 0, or 1 substituent that is halogen, (C 1 -C 6 )alkoxy, cyano, or hydroxy; or
R 7 is hydrogen or (C 1 -C 6 )alkyl that is substituted with 0, or 1 substituent that is halogen, (C 1 -C 6 )alkoxy, cyano, or hydroxy; and R 8 taken together with the nitrogen to which it is attached and taken together with R 3a and the carbon to which it is attached form a (4- to 6-membered)heterocycloalkyl that is substituted with 0, 1, or 2 substituents independently selected from halogen, hydroxy, (C 1 -C 3 )alkyl, halo(C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, and halo(C 1 -C 6 )alkoxy; or
R 7 and R 8 taken together with the nitrogen to which they are attached form a (4- to 6-membered)heterocycloalkyl that is substituted with 0, 1, or 2 substituents independently selected from halogen, hydroxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, and halo(C 1 -C 6 )alkoxy;
R 3a is hydrogen, or (C 1 -C 3 )alkyl that is substituted with 0 or 1 substituent that is hydroxy, or (C 1 -C 3 )alkoxy;
R 3b is hydrogen, or (C 1 -C 3 )alkyl, provided that R 3a and R 3b are not both H when R 4 is (R 4 -i);
R 4 is (R 4 -i) or (R 4 -ii):
wherein:
R 4N is (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, or (C 3 -C 6 )cycloalkyl, wherein said (C 1 -C 6 )alkyl is substituted with 0 or 1 substituent that is hydroxy;
R 4C is hydrogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, or (C 3 -C 6 )cycloalkyl, wherein said (C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkyl are substituted with 0 or 1 substituent that is hydroxy, cyano, or (C 1 -C 6 )alkoxy;
R 4D is hydrogen, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, or (C 3 -C 6 )cycloalkyl, wherein said (C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkyl are substituted with 0 or 1 substituent that is hydroxy, cyano, or (C 1 -C 6 )alkoxy;
R 4E is hydrogen, halogen, cyano, hydroxy, or (C 1 -C 6 )alkyl; and
R 4F is hydrogen, halogen, cyano, hydroxy, (C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, halo(C 1 -C 6 )alkoxy, or (C 3 -C 6 )cycloalkyl, wherein said (C 1 -C 6 )alkyl and halo(C 1 -C 6 )alkyl are substituted with 0 or 1 substituent that is hydroxy, cyano, or (C 1 -C 6 )alkoxy.
2. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is (R 4 -i);
R 4N is (C 1 -C 6 )alkyl, or (C 3 -C 6 )cycloalkyl; and
R 4C is hydrogen, or (C 1 -C 3 )alkyl.
3. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —N(R 5 )(R 6 ), or (C 3 -C 6 )cycloalkyl, wherein said (C 3 -C 6 )cycloalkyl is cyclopropyl and is substituted with 0 or 1 substituent that is (C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is methyl;
R 5 and R 6 are each independently hydrogen or (C 1 -C 3 )alkyl, or
R 5 and R 6 taken together with the nitrogen to which they are attached form a (5-membered)heterocycloalkyl that is substituted with 0, or 1 substituent that is (C 1 -C 6 )alkyl;
R 2 is N(R 7 )(R 8 ), wherein R 7 and R 8 are each independently hydrogen or (C 1 -C 6 )alkyl that is methyl;
R 3a is (C 1 -C 3 )alkyl that is substituted with 0 or 1 substituent that is (C 1 -C 3 )alkoxy; and
R 3b is hydrogen, or (C 1 -C 3 )alkyl.
4. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is (R 4 -ii);
R 4D is hydrogen, (C 1 -C 6 )alkyl, or halo(C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is substituted with 0 or 1 substituent that is hydroxy;
R 4E is hydrogen; and
R 4F is hydrogen, (C 1 -C 6 )alkyl, or halo(C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is substituted with 0 or 1 substituent that is hydroxy.
5. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is —N(R 5 )(R 6 ), or (C 3 -C 6 )cycloalkyl, wherein said (C 3 -C 6 )cycloalkyl is cyclopropyl and is substituted with 0 or 1 substituent that is (C 1 -C 6 )alkyl, wherein said (C 1 -C 6 )alkyl is methyl;
R 5 and R 6 are each independently hydrogen or (C 1 -C 3 )alkyl, or
R 5 and R 6 taken together with the nitrogen to which they are attached form a (5-membered)heterocycloalkyl that is substituted with 0, or 1 substituent that is (C 1 -C 6 )alkyl;
R 2 is N(R 7 )(R 8 ), wherein R 7 and R 8 are each independently hydrogen or (C 1 -C 6 )alkyl that is methyl;
R 3a is hydrogen, or (C 1 -C 3 )alkyl that is substituted with 0 or 1 substituent that is (C 1 -C 3 )alkoxy; and
R 3b is hydrogen, or (C 1 -C 3 )alkyl.
6. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 1 is 2-methyl-pyrrolidin-1-yl, or 2(R)-methyl-pyrrolidin-1-yl.
7. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 and R 8 are each hydrogen.
8. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 7 is hydrogen; and R 8 is (C 1 -C 3 )alkyl.
9. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 35 is hydrogen, and wherein orientation of R 2 , R 3a , and R 3b provide a compound of Formula I(R) or Formula I(S):
10. The compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein R 4 is 5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl, (5R)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl, (5.5)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl, 5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl, (5S)-5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl, or (5R)-5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl.
11. The compound of claim 10 , or a pharmaceutically acceptable salt thereof, wherein R 4 is (5S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl, or (5S)-5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl.
12. A compound that is 4-[1-aminopropyl]-2-{6-[5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl}-6-[2-methylpyrrolidin-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
4-[1-aminoethyl]-2-{6-[5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl}-6-[2-methylpyrrolidin-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
4-[1-aminoethyl]-2-{6-[5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1s,2,4]triazol-3-yl]pyridin-2-yl}-6-[2-methylpyrrolidin-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
4-[1-aminoethyl]-2-{6-[5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl}-6-[methyl(propan-2-yl)amino]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
4-[1-aminopropyl]-2-{3-[5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]phenyl}-6-[methyl(propan-2-yl)amino]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; or
4-[1-amino-2-methoxyethyl]-6-(1-methylcyclopropyl)-2-{6-[5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; or a pharmaceutically acceptable salt thereof.
13. The compound of claim 12 , wherein the compound is 4-[(1R)-1-aminopropyl]-2-{6-[(5S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl}-6-[(2R)-2-methyl pyrrolidin-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
4-[(1R)-1-aminoethyl]-2-{6-[(5S)-5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl}-6-[(2R)-2-methylpyrrolidin-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
4-[(1S)-1-aminoethyl]-2-{6-[(5S)-5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl}-6-[(2R)-2-methylpyrrolidin-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
4-[(1R)-1-aminoethyl]-2-{6-[(5S)-5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl}-6-[methyl(propan-2-yl)amino]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
4-[(1R)-1-aminopropyl]-2-{3-[(5S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]phenyl}-6-[methyl(propan-2-yl)amino]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one;
4-[(1R)-1-amino-2-methoxyethyl]-6-(1-methylcyclopropyl)-2-{6-[(5S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; or
4-[(1S)-1-amino-2-methoxyethyl]-6-(1-methylcyclopropyl)-2-{6-[(5S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl}-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; or a pharmaceutically acceptable salt thereof.
14. A compound having the structure:
15. A compound that is 4-[(1R)-1-aminopropyl]-2-{6-[(5S)-5-methyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl}-6-[(2R)-2-methylpyrrolidin-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; or a pharmaceutically acceptable salt thereof.
16. A compound that is 4-[(1R)-1-aminoethyl]-2-{6-[(5S)-5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl}-6-[(2R)-2-methylpyrrolidin-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; or a pharmaceutically acceptable salt thereof.
17. A compound that is 4-[(1.5)-1-aminoethyl]-2-{6-[(5S)-5-ethyl-6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazol-3-yl]pyridin-2-yl}-6-[(2R)-2-methylpyrrolidin-1-yl]-2,3-dihydro-1H-pyrrolo[3,4-c]pyridin-1-one; or a pharmaceutically acceptable salt thereof.
18. A pharmaceutical composition comprising a compound of claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
19. A method for the treatment of cancer abnormal cell growth in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1 , or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, bladder cancer, uterine cancer, prostate cancer, lung cancer, esophageal cancer, head and neck cancer, colorectal cancer, kidney cancer, liver cancer, pancreatic cancer, stomach cancer, and thyroid cancer.
20. The method of claim 19 , wherein the cancer is breast cancer.
21. The method of claim 19 , wherein the cancer is ovarian cancer.
22. The method of claim 19 , wherein the cancer is bladder cancer.
23. The method of claim 19 , wherein the cancer is uterine cancer.
24. The method of claim 19 , wherein the cancer is prostate cancer.
25. The method of claim 19 , wherein the cancer is lung cancer.
26. The method of claim 19 , wherein the cancer is esophageal cancer.
27. The method of claim 19 , wherein the cancer is head and neck cancer.
28. The method of claim 19 , wherein the cancer is colorectal cancer.
29. The method of claim 19 , wherein the cancer is kidney cancer.
30. The method of claim 19 , wherein the cancer is liver cancer.
31. The method of claim 19 , wherein the cancer is pancreatic cancer.
32. The method of claim 19 , wherein the cancer is stomach cancer.
33. The method of claim 19 , wherein the cancer is thyroid cancer.